Dendritic cells (DC) are antigen (Ag) presenting cells (APC) that initiate and regulate immune responses depending upon their state of differentiation (Banchereau et al. (2000) Annu. Rev. Immunol. 18:767-811). In transplantation, donor and recipient DC are known to be key initiators of anti-graft immune responses. Donor DC have been implicated in initiation of acute graft rejection by priming host T cells through the direct pathway of allorecognition while host DC promote chronic rejection by cross-presenting donor Ag to host T cells (Lechler et al. (2001) Immunity 14:357-368). There has been great interest in using DC to induce peripheral tolerance after organ transplantation (Morelli et al. (2007) Nat. Rev. Immunol. 7:610-621; van Kooten et al. (2011) Transplantation 91(1):2-7). Adoptive transfer of immature dendritic cells (imDC) in transplant (Tx) models has been shown to prolong graft survival (Lu et al. (1995) Transplantation 60:1539-1545; Fu et al. (1996) Transplantation 62:659-665; Lutz et al. (2000) Eur. J. Immunol. 30(7):1813-1822).
Activation of T cells requires both major histocompatibility complex (MHC)-antigen peptide recognition by the T cell receptor and costimulation by APC. Freshly-isolated imDC fail to activate T cells due to low expression of MHC and costimulatory molecules. The nature of the stimulation (e.g., inflammatory cytokines, bacterial/viral constituents, or T cell products) or the environment in which DC are stimulated (e.g., liver) may influence the type of T cell response induced (e.g., T helper (Th)1, Th2, Th17, and regulatory T (Treg)). Treg cells include CD4+, CD25+ (IL-2 receptor α-chain) and transcription factor forkhead box P3 (FOXP3)+ and are naturally present in the immune system. They are required to maintain self-tolerance and regulate immune homeostasis. They are able to suppress the activation, proliferation and effector functions of numerous immune cells, including DC.
The function of hepatic dendritic cells (HDC) is particularly interesting given their unique function compared to DC from other sites. HDC monitor portal blood which is rich in gut-derived Ag and bacterial products such as lipopolysaccharide (LPS). These DC are therefore specialized to distinguish foreign pathogens from self or food Ag and to instigate tolerance or the appropriate immune response.
The microenvironment within which HDC reside and are activated also plays an important role. The liver is rich in immunomodulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β which likely have important influences on activation and function of HDC (Lee et al. (1998) Transplantation 66:1810-1817; Takayama et al. (1998) Transplantation 66:1567-1574). The allostimulatory activity of imHDC for memory T cells is refractory to pro-inflammatory cytokines, but adding Ag to immature HDC induces upregulation of MHC II, costimulatory molecules, and T cell allostimulatory activity (Abe et al. (2001) J. Hepatol. 34:61-67). In vivo administration of murine imHDC to allogeneic recipients selectively increases IL-10 production in secondary lymphoid tissue (Khanna et al. (2000) J. Immunol. 164:1346-1354). Moreover, it has been shown that HDC promote CD4 T cell hyporesponsiveness and increased Treg (Bamboat et al. (2009) J. Immunol. 182:1901-1911). Plasmacytoid (p)DC are type-1 interferon (IFN)-producing cells that have been identified in humans (Siegal et al. (1999) Science 284:1835-1837; Cella et al. (1999) Nat. Med. 5:919-923) and mice (Bjorck et al. (2001) Blood 98:3520-3526; Asselin-Paturel et al. (2001) Nat. Immunol. 2:1144-1150; Nakano et al. (2001) J. Exp. Med. 194:1171-1178) as a subset of DC which can induce tolerance (Matta et al. (2010) Eur. J. Immunol. 40:2667-2676). Studies of HDC show a higher frequency of pDC in the liver compared to the spleen (Pillarisetty et al. (2004) J. Immunol. 172:1009-1017).
Micro-ribonucleic acid (miRNA, miR) are short RNA molecules, typically 15-22 nucleotides in length, which can post-transcriptionally regulate messenger RNA transcripts, resulting in translational repression or upregulation (Anglicheau et al. (2010) Transplantation 90:105-112). Currently, miRNA antagonists or mimics are being used therapeutically in cancer and other diseases, such as inflammation and cardiovascular disease (Kasinski et al. (2011) Nat. Rev. Cancer 11:849-864; van Rooij et al. (2012) Nat. Rev. Drug Discov. 11:860-872).
There remains a need in the art for better methods of controlling immune responses for treating immune diseases and conditions, such as transplant rejection, inflammatory disorders, autoimmune diseases, allergies, infectious diseases, immunodeficiency, and cancer.